Tkialkylacetamides having satu



Patented Jan. 16, 1940 UNITEDSTATES PATENT OFFlCE TRIALKYLACE TAIHIDESHAVING SATU- RATED ALKYL GROUPS AND A METHOD OF MAKING THE SAME KarlJunkmanm Berlin, and Hans-Georg Allardt, Philippsthal, Kreis Teltow,Germany, assignors to Schering Aktiengesellschaft, a corporation ofGermany No Drawing. Application January 8,

Serial No. 119,658. In Germany August 16,

10Claims. (01.260 66!) This invention relates to trialkylacetamideshaving saturated alkyl groups and a method of making the same.

By the researches of Fromherz, Arch. -f. exp. Pathologie undPharmakologie, vol. 1'73, page 78, it has become known that thesubstituted acetamides possess peripheral paralysing (spasmolytic)properties. This assertion is accompanied on page 83 by three examples,which are, however, only very weakly active acetamides.

The present invention is based on the discovery that the tertiarysaturated alkyl substitutedacetic acid amides with from 12 to 17C-atoms,

' manufactured according to known processes from tertiary nitriles ofthe general formula:

R" g in which R, R and R" indicate the same or different saturated alkylgroups such that in the case of the saturated trialkylaceta'mides with12 carbon atoms R, R and R" constitute alkyls with at least 3 carbonatoms, compared with those described by Fromherz exhibit an unexpectedlygood spasmolytic action. I

By comparing the different trialkylacetamides on a superior rabbitintestine maintained permanently in Tyrode solution containing barium,the individual preparations being standardised against novocainehydrochloride as comparative preparation, the following results areobtained:

Activity number papaverino HO]- solution=l00 Acetamide examined C-numberI. Saturated triallcylacetamides containing up to ZZJ-C-atams Methyl-diethyl-ace tamide iiiiiiiii Triethyl-acetamideDiethyl-n-propyl-acetamide i Methyl-dipropyl-acotamideEthyl-clipropyl-acetamide Diethyl-butyl-acetamide. Tripropyl-acetamide.i Ethyl-dibutylacetamides i H; Unsaturated trialkylacetamidas containingup to IZ-C-utoms Diethyl-allyl-acetamidc M othyl-diallyl-acetamide i.Ethyl-diallyl-acetamide. i n-Propyl-diallyl'acetainide iIsopropyl-diallyl-acetamide i n-Butyl-dia]lyl-aoetamide'Iriallyl-acetamide Activitynumber papaverine H01- solution=l00Acetamide examined O-number III. Saturated trialkylacetamides contaming12-17- C-atoms (according to the invention) Dipropyl-butyl-acetamide -l2100. Propyl-dibutyl-acetamide 13 110 Tributyl-acetamide i. 14 130Ethyl-di-isoamyl-acetamide. 14 187. 5 Ethyl-dihexyl-acetamide 16 125. OTri-isoamyl-acetamide 17 125. 0 Propyl-diamyl-acetamide. 15 125. 0Butyl-diainyl-acetamide 8 Dibutyl-amyl-acetamide In these experimentsnovocaine' hydrochloride was equal to 1/75 papaverine hydrochloride. It

- was thereforepossible by a simple calculation to bring thenumbers'obtained into relation with those given by Fromherz'; who usespapaverine as standard and makes this equal to 100.

From this table .it ,is clearly "seen that the strong effects obtainedwith the tertiary saturated amides of this invention were not to beforeseen. v

In addition it should be remarked that the hitherto known acetamideswith small C-number examined by Fromherz are fairly strong scporifics,while the new substances according to the present invention even inlarge doses have practically 'no soporific effect which is extremelyseparating extracted with a solvent immiscible with water, for example,benzene, the extract washed with sodium carbonate solution and the amideproduced therefrom in the customary manner. It is separated from smallquantities of starting material by vacuum distillation. The amide hasthe B. P. 176 C. under 16 mm. pressure, the M. P. 69 to 70 C. andconstitutes a white crystal powder which easily dissolves in ether,alcohol, petrol-ether and benzene.

o H N Found 73. 47 12.8 6.9 Calculated 13.2 12. 6. 5s

The hydrolysis can be carried out instead of with sulphuric acid byheating with water to 180 to 200 C., if desired with the addition of anemulsifying agent such as the sodium salt ofdi-isopropylnaphthalene-B-su1phonic acid.

(b) 19.5 parts of di-n-butyl-n-pr0pyl-acetonitrile are dissolved in 200parts of alcohol and 48 parts of 10% hydrogen peroxide and 0.8 part ofcaustic soda in a little Water added. The whole is heated with stirringgradually to 40 to 60 C., neutralised after completion of the hydrolysiswith acid and the alcohol evaporated. The residue recrystallised fromdilute alcohol yields white needles of M. P. 69-'70 C., the puredibutyl-propyl-acetamide.

Example 2 50 parts of tri-n-butyl-acetonitrile B. P. 142 to 146 C. under17 mm. pressure, 300 parts of butyl or amyl alcohol and 60 parts ofpotassium hydroxide in 10 parts of water are boiled with stirring undera reflux condenser for hours, the alcohol is thereupon removed by steamdistillation and the residue extracted with benzene. From the benzenesolution is obtained in the customary manner the amide, which passesover in a vacuum of 12 mm. at 183 C. It solidifies to white needleswhich have the M. P. 60 to 61 C. It is easily soluble in ether,petrol-ether benzene, alcohol, and chloroform, insoluble in water.

For acceleration of the saponification it can be carried out suitably inautoclaves at a temperature of 150 to C. Otherwise the process isconducted as set forth above.

Example 3 Triisoamyl acetonitrile, obtained according to U. S. Patent1,958,653 from acetonitrile, sodium amide and isoamyl bromide, yields onsaponification triisoamyl acetamide of the boiling point 198 C. at avacuum of 14 mm. and the melting point 67 to 685 C. It crystallizes frompetrol ether in White platelets.

Of course, in a similar manner other saturated trialkylacetamides havingat least 12 and at most 17 carbon atoms in the molecule may be obtainedfrom the corresponding trialkylacetonitriles.

What we claim is:

1. A process for the manufacture of a trialkylacetamide with saturatedalkyl groups and of strong spasmolytic action, comprising saponifyingtri-n-butyl acetonitrile to the corresponding acetamide.

2. Tri-n-butyl acetamide of the general formula CmHzcON and the meltingpoint 60-61 C.

3. A process for the manufacture of substances having a high spasmolyticaction, comprising hydrolyzing tertiary nitriles with at least 12 and atmost 17 carbon atoms in the molecule, of the general formula:

atoms in the molecule, of the general formula:

RI! in which R, R and R" indicate saturated alkyl groups all higher thanmethyl, at least two of such groups having at least four carbon atoms.

5. A trialkylacetamide of strong spasmolytic action having at least 12and at most 1'7 carbon atoms in the molecule, and of the generalformula:

a ccoum R in which R, R and R" indicate saturated alkyl groups, at leasttwo of such groups having at least four carbon atoms.

6. As a spasmolytic agent, and trialkylacetamide of strong spasmolyticaction having more than 12 but no more than 17 carbon atoms in themolecule, and of the general formula:

w-coozvm in which R, R and R" indicate saturated alkyl groups all higherthan methyl.

'7. A trialkylacetamide of strong spasmolytic action of the generalformula:

in which R, R and R indicate saturated alkyl groups, at least two ofsuch groups having each at least 4 carbon atoms and the third at least 3carbon atoms, the total number of carbon atoms in the compound notexceeding 1'7.

8. A trialkylacetamide of strong spasmolytic action of the generalformula:

rv-ccoxm in which R, R and R" indicate saturated alkyl groups of 3 to 5carbon atoms, at least two of such groups having more than 3 but no morethan 5 carbon atoms.

9. As a spasmolytic agent, n-propyl-di-n-butyl acetamide of the generalformula C13H2'1ON and the melting point 69-70 C. from dilute alcohol.

10. As a spasmolytic agent, tri-isoamyl acetamide of the general formulaC1'1H35ON and the melting point 67-68.5 C.

KARL JUNKMANN. HANS-GEORG ALLARDT.

